Injuries of the spinal cord and/or brain occur relatively often in traffic or sports accidents. Depending on the degree or severity of these traumata, more or less pronounced symptoms develop (such as paraplegia or paralysis due to spinal cord injuries or central paralysis, impairment of the memory and other neurological deficiencies due to traumata of the brain) which often are irreversible and in any case are difficult to cure. Faden et al., in New England Journal of Medicine, Vol. 305, No. 18, pp. 1063-67, reported that thyrotropin-=releasing-hormone (TRH=L-pyroglutamyl-L-histidyl-L-prolinamide) significantly improves recovery of the motoric function after experimental spinal cored injury in animal experiments when treatment occurs during the first 24 hours following the trauma. Fukuda et al., in Nippon Yakurigaku Zasshi, Vol. 75, No. 4, pp. 321.varies.31 observed a dose-dependent positive effect of TRH in animal experiments on EEG alterations resulting from traumata of the brain caused by brain stem compression in cats. Takahashi et al., U.S. Pat. No. 4,059,692, teaches that impaired consciousness in humans due to functional or organic damage of the brain, such as cranial trauma, cerebrovascular disorder, cerebral surgery or brain tumor, may be improved by administration of TRH successively for at least 10 days.
Unfortunately, in living organisms TRH is quickly metabolized and inactivated by enzymatic cleavage of the pyroglutamyl group and/or deamidation. Accordingly, TRH or a salt thereof is generally administered by continuous intravenous infusions in high doses, and only in exceptional cases is intramuscular or peroral administration considered.
Attempts have been made to synthesize, by chemical modification of the TRH-molecule, compounds which have the desired biological activities of TRH but which are stable against the metabolizing and inactivating enzymes and which thus avoid the disadvantages of TRH resulting from its instability. See: Metcalf, "The Neuropharmacology of TRH Analogues," Thyrotropin-Releasing Hormone: Griffiths et al, eds.; Raven Press, New York, (1983). These TRH-modifications show, however, different profiles of biological activity, and, in particular, their activities are only partially equivalent to those of TRH. These results were ascertained, however, only with respect to the endocrinological effects and to the stimulating effects on the central nervous system. Accordingly it is completely unknown and unpredictable whether such TRH-modifications have any effects - and, if so, which effects they may have - on posttraumatic nervous injuries, especially on paraplegia due to spinal cord injuries and/or on neurological deficiencies after traumata of the brain.
compounds corresponding to the formula I: ##STR3## wherein
R.sub.1 represents a hydrogen atom, an alkyl group containing one to six carbon atoms, a cyclohexyl group or a benzyl group,
Z is one of the following groups (attached to the CO-group in the ring by the valence marked with an asterisk): ##STR4##
if Z represents a group (a), R.sub.2 l and R.sub.3 represent an additional bond between the carbon atoms to which R.sub.2 `and R.sub.3 are attached, or if Z represents a group (b), R.sub.2 is a hydrogen atom,
R.sub.4 and R.sub.5 are the same or different and each represents hydrogen or an alkyl group containing one to three carbon atoms and wherein R.sub.5 also may represent a phenyl group and
R.sub.6 represents a hydrogen atom or a methyl group. The compounds of formula I (as well as hydrates and acid addition salts thereof,) and their preparation have been described e.g., by Schwertner et al. in "Structure and Activity of Natural Peptides'" (Editors W. Voelter and G. Weitzel), Walter de Gruyter-Verlag, Berlin - New York, 1981, pp. 397-415, in U.S. Pat. No. 4,045,556, in British Pat. No. 1,564,078, the disclosures of which are incorporated herein by reference, and elsewhere.
The aforementioned publications disclose that the compounds of formula I on parenteral or oral administration provide long lasting central nervous system stimulating effects and that the toxicity of the compounds is very low. Due to these pharmacological properties, the compounds of formula I according to the publications mentioned above and further references can be used as psycho-stimulating agents or as antidepressive agents. Accordingly the known fields of application for the compounds of formula I relate only to chronic metal illness and not to acutely occurring neurological injuries. It was unforeseeable that the compounds of formula I or medicaments containing them could be used for treatment of posttraumatic nervous injuries, especially to prevent or to treat paraplegia due to spinal cord injuries and/or neurological deficiencies after traumata of the brain.